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Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain. To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase. We found that 13% of the Severe Asthma Research Program-3 cohort is \"eDNA-high,\" as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all values <0.001). In studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase. High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.

The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with “off-target” inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.

Estrogen receptor α (ERα) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol (E ) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown. We hypothesized that knockdown (KD) of ERα expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis. We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced E at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ERαKD, receiving selective ERα gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS-elements computer software quantification of ERα knockdown. ERα expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ERαKD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ERα-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption. ERα activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control.

Context: Estrogen receptor [alpha] (ER[alpha]) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol ([E.sub.2]) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown. Objective: We hypothesized that knockdown (KD) of ER[alpha] expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis. Methods: We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced [E.sub.2] at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ER[alpha]KD, receiving selective ER[alpha] gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS- elements computer software quantification of ER[alpha] knockdown. Results: ER[alpha] expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ER[alpha]KD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ER[alpha]-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption. Conclusion: ER[alpha] activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control. Key Words: ventromedial nucleus, arcuate nucleus, female sexual dysfunction, hypergonadotropism, hyperglycemia, diet- induced obesity Abbreviations: 3D, 3-dimensional; 17-OHP4, 17-hydroxyprogesterone; AAV, adeno-associated virus; ARC, arcuate nucleus; ARCd, arcuate nucleus dorsal; ARCv, arcuate nucleus ventral; AUC, area under the curve; BMC, bone mineral content; BMD, bone mineral density; CG, chorionic gonadotropin; CMV, cytomegalovirus; DHEA, dehydroepiandrosterone; DIO, diet-induced obesity; DXA, dual-energy x-ray absorptiometry; [E.sub.2], estradiol; EIA, enzyme immunoassay; ER[alpha], estrogen receptor [alpha]; ER[alpha]KD, estrogen receptor [alpha] knockdown; FFM, fat free mass; GFP, green fluorescent protein; GnRH, gonadotropin-releasing hormone; IM, intramuscular; ir, immunoreactive; KD, knockdown; KO, knockout; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LET, letrozole; LH, luteinizing hormone; MBH, mediobasal hypothalamus; mPOA, medial preoptic area; MRI, magnetic resonance imaging; NHP, nonhuman primate; OGTT, oral glucose tolerance test; OVX, ovariectomy; POA, preoptic area; POMC, pro- opiomelanocortin; RC, rostral-caudal; RNAi, RNA interference; ROI, region of interest; SC, subcutaneous; SF1, steroidogenic factor-1; shRNA, short hairpin RNA; siRNA, small interfering RNA; VMN, ventromedial nucleus; VMNm, ventromedial nucleus mid; VMNv, ventromedial nucleus ventral.

A retrospective audit was conducted on selected medical records of patients (pts) hospitalized in 1996 and 1997 diagnosed as malnourished (159 pts) or Type 2 Diabetes Mellitus (DM) (203 pts). For malnourished pts, energy intake level was significantly higher in those receiving MNT than those not seen (p=0.006) and larger gains were seen with higher levels of MNT (χ2=24.2, p=0.004). Provision of MNT was not associated with improvement in pt weight (p- 0.065), serum levels of albumin (p=0.067) or prealbumin (N=4, no analysis), nor incidence of complications (N=7, no analysis), but inadequate data availability limited the outcomes analysis. Only 20% of the records contained both admission and discharge weights, and only 30% contained serial measures of serum proteins. The degree of malnutrition was not associated with the level of MNT provided (χ2=5.6, p=0.428) . For patients with DM, weight decreased by >3# with MNT provided compared to <1# in those not seen, although the difference was not significant (p=0.399). Comparison weights were available for only 35% of pts. MNT was not significantly associated with change in blood glucose (p=0.220). To few charts contained serial Hgb Ale or triglycerides for analysis. Mean length of stay was not reduced with provision of MNT in either of these patient populations, in fact, MNT was associated with increased LOS (p-0.000 for malnutrition, p=0.003 for DM). This probably indicates that the longer a pt is hospitalized, the more MNT is provided.